Pyrazole inhibitors of HMG-CoA reductase: an attempt to dramatically reduce synthetic complexity through minimal analog re-design.

Pyrazole inhibitors of HMG-CoA reductase: an attempt to dramatically reduce synthetic complexity through minimal analog re-design. Research Abstract Details 

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Pyrazole inhibitors of HMG-CoA reductase: an attempt to dramatically reduce synthetic complexity through minimal analog re-design. Abstract Text:

Scott D Larsen,Toni-Jo Poel,Kevin J Filipski,Jeffrey T Kohrt,Jeffrey A Pfefferkorn,Roderick J Sorenson,Bradley D Tait,Valerie Askew,Lisa Dillon,Jeffrey C Hanselman,Gina H Lu,Andrew Robertson,Catherine Sekerke,Mark C Kowala,Bruce J Auerbach,Scott D Larsen,Toni-Jo Poel,Kevin J Filipski,Jeffrey T Kohrt,Jeffrey A Pfefferkorn,Roderick J Sorenson,Bradley D Tait,Valerie Askew,Lisa Dillon,Jeffrey C Hanselman,Gina H Lu,Andrew Robertson,Catherine Sekerke,Mark C Kowala,Bruce J Auerbach,

An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity.

Pyrazole inhibitors of HMG-CoA reductase: an attempt to dramatically reduce synthetic complexity through minimal analog re-design. Publishing Authors By Initials

SD Larsen,TJ Poel,KJ Filipski,JT Kohrt,JA Pfefferkorn,RJ Sorenson,BD Tait,V Askew,L Dillon,JC Hanselman,GH Lu,A Robertson,C Sekerke,MC Kowala,BJ Auerbach,SD Larsen,TJ Poel,KJ Filipski,JT Kohrt,JA Pfefferkorn,RJ Sorenson,BD Tait,V Askew,L Dillon,JC Hanselman,GH Lu,A Robertson,C Sekerke,MC Kowala,BJ Auerbach,

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Pyrazole inhibitors of HMG-CoA reductase: an attempt to dramatically reduce synthetic complexity through minimal analog re-design. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Bioorganic & medicinal chemistry letters

VOLUME: 17

Page Numbers: 5567-72

Journal Abbreviation: Bioorg. Med. Chem. Lett.

ISSN: 0960-894X

DAY: 11

MONTH: 08

YEAR: 2007

Pyrazole inhibitors of HMG-CoA reductase: an attempt to dramatically reduce synthetic complexity through minimal analog re-design. Information

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LANGUAGE: eng

NlmUniqueID: 9107377

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Grant and Affiliation Information for Pyrazole inhibitors of HMG-CoA reductase: an attempt to dramatically reduce synthetic complexity through minimal analog re-design.

AFFILIATION: Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. sdlarsen@umich.edu

Country: England

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MEDLINETA: Bioorg Med Chem Lett

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